Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.
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PMID:Congenital heart disease caused by mutations in the transcription factor NKX2-5. 967 15

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.
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PMID:GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. 1009 97

A homeobox-containing transcription factor Csx/Nkx2-5 is an important regulator of cardiac development. Many different human CSX/NKX2-5 mutations have been reported to cause congenital heart disease. We here examined the effects of three representative CSX/NKX2-5 mutations on cardiomyocyte differentiation and death with the use of the P19CL6 cardiomyogenic cell lines. Stable overexpression of wild-type CSX/NKX2-5 enhanced expression of cardiac-specific genes such as MEF2C and MLC2v, the promoter activity of the atrial natriuretic peptide gene, and the terminal differentiation of P19CL6 into cardiomyocytes, while all CSX/NKX2-5 mutants attenuated them by different degrees. When exposed to H(2)O(2) or cultured without change of the medium, many differentiated P19CL6 cells overexpressing the mutants, especially the mutant which lacks the carboxyl terminal region just after the homeodomain, were dead, while most of the cells overexpressing wild-type CSX/NKX2-5 survived. Overexpression of the carboxyl terminus-deleted mutant down-regulated expression of an anti-apoptotic protein Bcl-x(L) and up-regulated that of a pro-apoptotic protein CAS, while in the cells overexpressing wild-type CSX/NKX2-5, expression of a pro-apoptotic protein RIP was reduced. Furthermore, overexpression of wild-type CSX/NKX2-5 decreased the number of H(2)O(2)-induced TUNEL-positive cultured cardiomyocytes of neonatal rats, whereas overexpression of the mutants enhanced it. These results suggest that Csx/Nkx2-5 not only regulates expression of cardiac-specific genes but protects cardiomyocytes from stresses and that cell death may be another cause for the cardiac defects induced by human CSX/NKX2-5 mutations.
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PMID:Dual effects of the homeobox transcription factor Csx/Nkx2-5 on cardiomyocytes. 1240 79

NKX2-5 is a homeodomain-containing transcription factor important in cardiac development. Familial mutations in the NKX2-5 gene are associated with cardiac abnormalities, but mutations are rare in sporadic cases. We studied the pathology and molecular genetics of NKX2-5 in diseased heart tissues of 68 patients with complex congenital heart disease (CHD), particularly atrial (ASD), ventricular (VSD), and atrioventricular septal defects (AVSD). We also studied DNA extracted from 16 normal hearts, as well as lymphocytic DNA from 50 healthy volunteers, 7 families, and 4 unrelated individuals with CHD. Direct sequencing revealed 53 NKX2-5 mutations in the diseased heart tissues, including nonsynonymous substitutions in the homeodomain of NKX2-5. We found common mutations among unrelated patients, but certain mutations were specific to VSDs and AVSDs. Many patients had multiple NKX2-5 mutations, up to 14 nonsynonymous mutations per patient in VSDs. Importantly, these nonsynonymous mutations were mainly absent in normal heart tissues of the same CHD patients, thus indicating somatic origin and mosaicism of mutations. Further, observed mutations were completely absent in normal hearts and lymphocytic DNA of healthy individuals. Our findings provide new insights for somatic NKX2-5 mutations to be of importance in congenital heart disease.
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PMID:Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. 1516 46

NKX2-5 is a pivotal transcription factor in heart development. Previous studies on lymphocytic DNA provided evidence of familial NKX2-5 gene mutations in cardiac malformations. Common mutations are rare in unrelated families. We analysed, by direct sequencing, the gene encoding NKX2-5 in the diseased heart tissues of 68 patients with complex congenital heart disease, focussing particularly on atrial, ventricular, and atrioventricular septal defects. We identified 35 non-synonymous NKX2-5 mutations in the diseased heart tissues of patients. These mutations were mainly absent in normal, for example, unaffected, heart tissue of the same patient, indicating the somatic nature and mosaicism of mutations. We also observed multiple mutations and multiple haplotypes, as well as mutations in Down's syndrome patients with cardiac malformations. Taken collectively, the above results suggest the somatic nature of NKX2-5 mutations associated with complex cardiac malformations. Somatic mutations in transcription factor genes of cardiac progenitor cells provide a novel mechanism of disease.
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PMID:Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. 1688 39

Human heart development requires an orderly coordination of transcriptional programs, with the homeodomain protein NKX2-5 being one of the key transcription factors required for the differentiation of mesodermal progenitor cells. Indeed, lack of Nkx2-5 in mice arrests heart development prior to looping, resulting in embryonic lethality. There are 28 germline NKX2-5 mutations identified in humans that are associated with congenital heart disease, and we recently reported multiple somatic mutations in patients with complex cardiac malformations. To address the functional consequences of single and multiple mutations of NKX2-5, we developed a functional assay in the budding yeast Saccharomyces cerevisiae, which could determine transactivation capacity and specificity of expressed NKX2-5 alleles towards targeted response element (RE) sequences. We focused on mutants of the third helix, which provides DNA binding specificity, and characterized mutations that were highly associated with either ventricular (VSD) or atrioventricular (AVSD) septal defects. Individual mutants exhibited partial to complete loss of function and differences in transactivation capacity between the various REs. The mutants also exhibited gene dosage rather than dominant effects on transcription. Surprisingly, all AVSD patients (22/23) had a single K183E mutation in the DNA binding domain, which resulted in transcriptional inactivation. None of the VSD patients had this mutation; yet 14/29 had at least one mutation in the third helix leading to either inactivation or reduction of NKX2-5 transactivation. Therefore, mutations of somatic origin in the binding domains of NKX2-5 were associated specifically with AVSD or VSD and resulted in loss of protein function.
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PMID:Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system. 1591 68

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
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PMID:Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. 1766 78

Through the use of animal studies, many candidate genes (mainly encoding transcriptional factors and receptors) have been implicated in the development of congenital heart disease. Thus far, only a minority of these genes have been shown to carry mutations associated with congenital disease in humans, e.g., GATA 4, TBX-5, NOTCH1 and NKX2-5. Mutations in these genes can cause a variety of cardiac defects even within the same family. Conversely, similar phenotypes are observed for different gene mutations suggesting a common pathway. Multiple genes and genetic pathways have been related to atrioventricular valve formation, although most of these genes have not yet been demonstrated as causative in human atrioventricular valve defects. Key pathways include the epidermal growth factor receptor pathway and related interacting pathways, most importantly the pathway of UDP-glucose dehydrogenase, resulting ultimately in activation of Ras. Other examples of interacting pathways include that of Nodal/Cited2/Pitx2, Wnt, Notch and ECE. Further studies are needed to investigate the pathways which are crucial for atrioventricular valve formation in humans. Understanding the underlying molecular process of abnormal atrioventricular valve formation in patients with congenital heart disease may provide important insight, in the etiology and possibly into preventive or treatment regimes.
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PMID:Genes in congenital heart disease: atrioventricular valve formation. 1839 68

Heart formation is a complex morphogenetic process, and perturbations in cardiac morphogenesis lead to congenital heart disease. NKX2-5 is a key causative gene associated with cardiac birth defects, presumably because of its essential roles during the early steps of cardiogenesis. Previous studies in model organisms implicate NKX2-5 homologs in numerous processes, including cardiac progenitor specification, progenitor proliferation, and chamber morphogenesis. By inhibiting function of the zebrafish NKX2-5 homologs, nkx2.5 and nkx2.7, we show that nkx genes are essential to establish the original dimensions of the linear heart tube. The nkx-deficient heart tube fails to elongate normally: its ventricular portion is atypically short and wide, and its atrial portion is disorganized and sprawling. This atrial phenotype is associated with a surplus of atrial cardiomyocytes, whereas ventricular cell number is normal at this stage. However, ventricular cell number is decreased in nkx-deficient embryos later in development, when cardiac chambers are emerging. Thus, we conclude that nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number. Our data suggest that morphogenetic errors could originate during early stages of heart tube assembly in patients with NKX2-5 mutations.
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PMID:Nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number. 1871 62

Mutations in homeoprotein NKX2-5 are linked to human congenital heart disease, resulting in various cardiac anomalies, as well as in postnatal progressive conduction defects and occasional left ventricular dysfunction; yet the function of Nkx2-5 in the postnatal period is largely unexplored. In the heart, the majority of cardiomyocytes are believed to complete cell-cycle withdrawal shortly after birth, which is generally accompanied by a re-organization of chromatin structure shown in other tissues. We reasoned that the effects of the loss of Nkx2-5 in mice may be different after cell-cycle withdrawal compared with those of the perinatal loss of Nkx2-5, which results in rapid conduction and contraction defects within 4 days after the deletion of Nkx2-5 alleles (Circ Res. 2008;103:580). In this study, floxed-Nkx2-5 alleles were deleted using tamoxifen-inducible Cre transgene (Cre-ER) beginning at 2 weeks of age. The loss of Nkx2-5 beginning at 2 weeks of age resulted in conduction and contraction defects similar to the perinatal loss of Nkx2-5, however, with a substantially slower disease progression shown by 1 degrees atrioventricular block at 6 weeks of age (4 weeks after tamoxifen injections) and heart enlargement after 12 weeks of age (10 weeks after tamoxifen injections). The phenotypes were accompanied by a slower and smaller degree of reduction of several critical Nkx2-5 downstream targets that were observed in mice with a perinatal loss of Nkx2-5. These results suggest that Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age, but with a substantially distinct level of necessity at 2 weeks of age compared with that in the perinatal period.
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PMID:Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation. 1954 53


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